1. Field
Provided is a pharmaceutical composition for combination therapy for an angiogenesis-associated disease, including a combination of an anti-c-Met antibody and an anti-Ang-2 antibody as an active ingredient.
2. Description of the Related Art
Angiogenesis is a physiological process through which new blood vessels form from pre-existing vessels. This is a normal and vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, it is also a fundamental step in the transition of tumors from a benign state to a malignant state, in the onset of various other diseases including age-related macular degeneration and diabetic retinopathy, and in driving psoriasis, rheumatoid arthritis, and chronic inflammation.
Particularly, angiogenesis plays a critical role in the growth and metastasis of tumors, leading to the use of angiogenesis inhibitors in the treatment of cancer. In fact, extensive and intensive research on angiogenesis has been conducted by advanced countries and multinational pharmaceutical companies to develop cancer therapeutics with this new concept. Many therapeutic targets have been disclosed by the research. Among them are angiopoietins, protein growth factors promoting vasculature development and post-natal angiogenesis. There are now four identified angiopoietins: Ang-1, Ang-2, Ang-3 and Ang-4.
Ang-2 is known as an antagonist ligand for Tie-2, a vascular endothelial cell-specific receptor tyrosine kinase (RTK), used to block Tie-2-mediated cell signaling. This ligand competes with the agonist ligand Ang-1 for binding to Tie-2, interfering with the Ang-1-Tie-2-mediated signaling which contributes to the stability of endothelial cells, and thereby promoting angiogenesis through the dynamic rearrangement of blood vessels.
Because angiogenesis plays an essential role in tumor growth, inhibition of Tie-2-dependent Ang-2 function is expected to prevent the progression of cancer. In practice, active research has been conducted using Ang-2-specific antibodies in an attempt to prevent the progression of cancer.
However, a recent report indicates that, in the presence of angiogenesis inhibitors such as anti-Ag2 antibodies, cancer cells are rather prone to metastasis as a result of the mechanism by which cancer cells avoid a rapid hypoxic condition (Nat Rev Clin Oncol. 2011 Mar. 1; 8(4): 210-21). Thus, a technique for inhibiting angiogenesis even in a hypoxic condition is needed to prevent side effects.